Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1994-11-30
1997-09-02
Higel, Floyd D.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
514 94, 514359, 514364, 514381, 514385, 514392, 514398, 514399, 514403, 548112, 548252, 5483235, A61K 31675, A61K 3141, A61K 31415, C12Q 100, A01N 59100
Patent
active
056630530
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The invention relates to the area of inflammatory mediators. The invention is based on the discovery that blocking a key enzyme responsible for arachidonate movement (or remodelling), Coenzyme A-independent transacylase (CoA-IT), inhibits the production of lipid mediators (free arachidonic acid, arachidonic acid metabolites, and platelet-activating factor (PAF)). It has been discovered that CoA-IT is required for the release of free arachidonic acid and the synthesis of arachidonic acid metabolites and PAF. As CoA-IT is involved in arachidonate phospholipid metabolism, and required for the release of free arachidonaic acid and the production of eicosanoids and PAF, inhibition of such would be useful for the treatment of disease states caused thereby.
BACKGROUND OF THE INVENTION
An early event in the response of most inflammatory cells to immunologic activation and other stimuli is the release of newly formed products (mediators) which alter the function and biochemistry of surrounding cells and tissues. The ensuing biological responses, as well as much of the pathogenesis which is attributed to inflammation and allergy, are thought to be dependent on the effects that these newly-formed. mediators have on adjacent cells within the inflammatory region.
In the last 20 years, it has become apparent that lipid mediators are among the most potent and important products which are generated during inflammatory reactions. The synthesis of most lipid mediators is initiated by the cleavage of complex phospholipid molecules which contain arachidonate at their sn-2 position. Free arachidonic acid is released from these phospholipids and this represents the rate-limiting step in the formation of eicosanoids (leukotrienes, prostaglandins and thromboxanes). As arachidonic acid is released, it is then converted to oxygenated derivatives by at least two enzymatic systems (lipoxygenase and/or cyclooxygenase). Concomitant with arachidonate release, lysophospholipids are formed. One of these lyso phospholipids, 1-alkyl-2-lyso-sn-glycero-3-phosphocholine, is then acetylated to form platelet-activating factor (PAF). Each of the cell types involved in the inflammatory response produce and secrete a unique subset of lipid mediators. The quantities and nature of the metabolites depend on which enzymes and precursor phospholipid pools are available to inflammatory cells.
Once lipid mediators such as PAF and eicosanoids are formed by the aforementioned pathways, they induce signs and symptoms observed in the pathogenesis of various inflammatory disorders. Indeed, the pathophysiological activity of arachidonic acid (and its metabolites) is well. known to those skilled in the art. For example, these mediators have been implicated as having an important role in allergy, asthma, anaphylaxis, adult respiratory distress syndrome, reperfusion injury, inflammatory bowel disease, rheumatoid arthritis, endotoxic shock, and cardiovascular disease. Aalmon and Higgs [Br. Med. Bull (1978) 43:285-296]; Piper et al. [Ann. NY Acad. Sci. (1991) 629:112-119]; Holtzman [Am. Rev. Respir. Dis. (1991) 143:188-203]. Snyder (Am. J. Physiol. Cell Physiol.) (1990) 259:C697-C708]; Prescott et al. [J. Biol. Chem. (1990) 265:17381-17384].
Similar to arachidonato products, PAF is a potent proinflammatory mediator produced by a variety of cells. In vitro, PAF stimulates the movement and aggregation of neutrophils and the release therefrom of tissue-damaging enzymes and oxygen radicals. PAF has also been implicated in activation of leukocytes, monocytes, and macrophages. These activities contribute to the actions of PAF as having (pathological) physiological activity in inflammatory and allergic responses. PAF has also been implicated in smooth muscle contraction, pain, edema, hypotensive action, increases in vascular permeability, cardiovascular disorders, asthma, lung edema, endotoxin shock, and adult respiratory distress syndrome. PAF elicits these responses either directly through its own cellular receptor(s) or indirectly by inducing
REFERENCES:
patent: 3021338 (1962-02-01), Bortnick
patent: 4355039 (1982-10-01), Niedballa et al.
patent: 5087634 (1992-02-01), Reitz et al.
patent: 5248689 (1993-09-01), Girard et al.
patent: 5256695 (1993-10-01), Poss
patent: 5338752 (1994-08-01), Hickey et al.
CA 116(25):255613, 19 Mar. 1992, Hickey et al.
CA 82(25):170937W, 1975, Jorgensen.
CA 117(3):26565, 19 Mar. 1992, Hickey et al.
CA 117(11):111 616JA, 19 Mar. 1992, Hickey et al.
CA 115(5):49682, 1991, Meanwell et al.
CA 112(6):42581b, 1989, Duerr.
CA 110(16):141549h, 1986, Schmitz et al.
CA 105(23):208887p, 1986, Lautenschlaeger et al.
Medline 92170539, 1991, Winkler et al.
Medline 911521139, 1991, Winkler et al.
CA 116(13):125547d, 1991, Suguira et al.
CA 115(17):177545a, 1991, Uemura et al.
Ninio et al., Regulation of the COA-Independent Transacylase in Human Neutrophils, Federation of European Biochemical Societies, Jul. 1991, pp. 138-140.
Chilton, III Floyd Harold
Hickey Deirdre Mary Bernadette
Winkler James David
Dinner Dara L.
Higel Floyd D.
Lentz Edward T.
SmithKline Beecham Corporation
The Johns Hopkins University
LandOfFree
Inhibition of inflammatory lipid mediators does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Inhibition of inflammatory lipid mediators, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Inhibition of inflammatory lipid mediators will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-307376